I disagree with most of this.

You seem to assume that aging has a bunch of root causes. We have a few lines of evidence that this is not the case for most of the core diseases of aging - I talk about this more in The Lens, Progerias, and Polycausality [? · GW]. Two particularly useful lines of evidence:

• Certain mutations or interventions seem to impact a bunch of core diseases of aging all at once - progerias, for instance. This shouldn't happen if there were lots of independent root causes.
• Many core diseases/aging markers are correlated even after adjusting for age. Again, this shouldn't happen if there are lots of independent root causes - different diseases/markers with different root causes shouldn't correlate after adjusting for age.

There are a bunch of "theories of aging" in the literature, but most of these do not seem likely to be root causes [? · GW] (although they may have seemed that way years ago). Some examples from your list:

• Inflammation was never a plausible root cause at all, since it isn't self-sustaining. The inflammaging theory just hypothesizes that inflammation plays some central role, not that it's a root cause.
• Loss of proteostasis was once hypothesized as a root cause (via an "error catastrophe" positive feedback loop). Now it's pretty clear the catastrophe version of the theory is wrong; proteostasis does get out of whack with age, but aging happens too slowly for it to be a root cause.
• We now know that most stem cells turn over normally. While counts of such cells can decrease with age, it isn't a root cause; something else must be causing failure of normal turnover and replacement.
• It now looks like telomere loss with age is mostly due to increased DNA damage rates, not a root cause.
• We now know that senescent cells normally turn over in ~2 weeks. While their count does increase with age, it isn't a root cause; something else must be increasing senescence rate or decreasing removal rate.

The purpose of research into the causes of aging is not to find more causes; it's to narrow down to the true root cause, and more generally to map out the gears of the system.

The section on targeted vs "phenotypic" approaches builds on the mistaken idea that aging has lots of root causes. For instance:

Phenotypic approaches also seem better suited to finding effective combinations of therapies, for the inelegant reason that biological systems are so interconnected that to find an effective combination therapy we’ll just have to try a lot of combinations. This is important for longevity, since it’s not clear how much partial credit we get for solving any single cause of aging. It may be that each one cured buys us more lifespan and eventually we reach longevity escape velocity. But since dying only requires one cause of death, we may need therapies that simultaneously address all or most causes of aging — even ones we don’t know of yet — before seeing benefits.

We actually do know how much partial credit we get for solving particular diseases of aging, e.g. cancer or heart disease. The answer is "barely any" - someone with age-related cancer is very likely to have heart disease or Alzheimers or some other disease within a few years even if they survive the cancer. However, we have evidence that there is one main root cause for all of these. So curing the root cause of one (not just fixing the symptoms) would probably cure the others as well. This means that combination treatments are unlikely to be very relevant, other than for (temporary) treatment of symptoms.

Also, on this:

The hard(er) part of building the atomic bomb wasn’t the nuclear physics, it was building the bomb, and I suspect longevity is similar.

The only reason that nuclear physics wasn't the hard part of the Manhattan project was that the key pieces had already been figured out, years before. That is not the case for aging, as of today.

You talk a lot about fundamentals and come to a conclusion about what projects should be funded on the margin. It seems to me that to make good calls about what should be funded on the margin we actually have to look about what money on the margin buys. 

It's a bit strange to call for less longevity research spending both complain that the FDA doesn't allow clinical trials when the clinical trial for aging that the FDA did approve is hold back by lack of funding.

With an $41.68 billion NIH budget it seems to me that paying 8-figures for a Metformin trial is on the margin a decent project even if we shouldn't expect that Metformin will add decades of life. 

The SENS Foundation seems to have a yearly budget of <5,000,000$. Funding it's research project with a 8 or 9-figure budget would also make sense to me. 

The talk about the list of limited causes of aging never really makes sense to me. Adult humans don't seem to grow new muscle cells and some muscle cells die over time. Given that the dead one don't get replaced, that seems to me like aging but it's not on the list. The list seems also very driven by molecular biology and doesn't include sensor motor amnesia with I consider on factor of aging. 

Despite how depressingly underrated longevity research is, technologies directly targeting the experience of suffering are underrated even more, with the possible exception of psychedelic therapy (by tech) and non-addictive painkillers (by pharma). 

That seems to me like a strange thing to say. A lot of pharma research goes into developing antidepressiva that help people who suffer a lot suffer less. There are also various people in mainstream psychology who think about how to get people to suffer less. 

The Manhatten project could easily do a test of whether their design worked. With aging we need to have a good enough theory to know whether any proxy measures we use to judge aging are actually good enough proxies or using them as outcomes for drugs is just Goodharting.

My reply comes a bit late since I managed to write a long comment without clicking send and only noticed this now. I will address the errors I see in the TL;DR summary from the POV of a semi-professional biogerontologist:

The disease-based approach to aging this seems to favour is useful, but limited. In fact, if you genuinely want to extend both lifespan and healthspan this excessive focus on the disease-based approach would be inefficient because is inconsistent with everything we know about aging. I would go as far as to say that the disease-based approach may be actively harmful because it takes away resources from genuine aging research.

While aging probably has thousands of causes, or even more*, this does not preclude the existence of major causes that limit lifespan in the near term.  This idea has been popularized by Aubrey de Grey a long time ago and now has reached the scientific mainstream with an emerging consensus about the Hallmarks of Aging (several key pathways and sequelae of aging). We also know that this view is decently well supported in mice and have known so since the late 1990s when Holly Brown-Borg and Andrzej Bartke introduced the Ames dwarf mouse to gerontology. If aging was strictly multifactorial and polygenetic there would be no hope to identify single genes that lead to pronounced lifespan extension, as they did with the long-lived Ames mouse, which is long-lived because of an underdeveloped pituitary and reduced growth hormone levels. This means one simple change to a single pathway can extend lifespan.

Of course, I am biased, since as a biogerontologist I think the biggest gains are to be had from targeting aging directly, although we can have a discussion how well the mouse data translates to humans. (Not well, IMHO, but it is the best we have.)

Sizable lifespan extension we have seen in mice has come, without exception, from interventions that target aging directly through the above discussed “hallmarks”. Just to give three famous examples of life extending treatments: We have Rapamycin, an inhibitor of the mTOR pathway, that became a plausible candidate after this pathway had been implicated in the aging of yeast. Then we have caloric restriction, which was discovered by accident and not by the disease-based approach, but is now known to target a global pathway that promotes tissue maintenance under nutrient stress. Finally, we also have senolytics, drugs that were developed to kill senescent cells, that had been linked with aging after decades of biogerontologic research.

In contrast, drugs like Aspirin, Simvastatin, Enalapril and many others were tested in mice with no clear biogerontologic rationale behind them and predictably failed to extend lifespan, even though they are obviously amazing from a disease-prevention point of view. 

However, I do agree that biogerontology depends on the existence of a strong biomedical ecosystem. Rapamycin was initially discovered as an immunosuppressant and if not for that, it would have taken longer to find inhibitors of the mTOR pathway (but eventually it would have happened by standard medicinal chemistry). Working in the 1930s Clive McKay, the discoverer of caloric restriction, was perhaps more interested in the basic biology of starvation and malnutrition than finding treatments for aging, etc.

Nothing about age-related multimorbidity makes sense if it not viewed through the lens of biogerontology.

Notes
* for example, you may be able to get 10-30% of lifespan extension by targeting the top 10 causes of aging, then eventually as you want to extend lifespan more and more, other causes of aging would take the spotlight

I should add that much of the most encouraging progress is in the area of xenotransplantation/stem cell transplantation, artificial organs, and neuronal replacement therapy (it's already being done for Parkinson's, though regeneration of the basal ganglia may be easier than regeneration of the entire brain - the https://gage.salk.edu/ lab is particularly good to follow on this). You don't need an entire mimic of the brain's memory or identity to maintain the continuity of consciousness.

https://www.nature.com/articles/s41536-017-0033-0?fbclid=IwAR2N4wjwAhHM3OXfGXV7QUNTUxFB3n275QO8-gDsA7qRkuL3ZeFVIrbyT5o https://www.frontiersin.org/articles/10.3389/fgene.2019.00310/full?fbclid=IwAR0RP6zGAUEBhphqk_t-rtIFEvHAo2c_PbPpmB-pPElnG20Tt1aiDx2vyLc

https://today.tamu.edu/2020/10/23/could-a-nasal-spray-of-nanovesicles-repair-brain-cells/?fbclid=IwAR0KP26TV-m4PWyhPs_PXMKNJIwWDwjulPtWndayJrdiNAqM2reUGgwkVM0

You don't need a full understanding of aging to safely transmit stem cells or tissue from one organism to another, and there are scientists who are working on the immunorejection problem wrt non-allogenic stem cells (eg see https://www.pnas.org/content/116/21/10441?fbclid=IwAR0LXoEBoZ_7THOj3szfW3rpqb-wDMv0xxFHFYcHstZfY3hZl2kDXgYHSuw ). 

Hell, some people [like Dave Asprey] already boldly inject themselves with stem cells (https://blog.daveasprey.com/how-adult-stem-cells-can-help-stop-pain-and-reverse-aging/ ) and while he doesn't know what the hell he's doing (and it seems like the FDA isn't even holding him back from this), the experimentation provides great evidence for the rest of us.

Gradual "chimerism" is an encouraging direction that does not require us to understand all kinds of age-related damage (eg https://twitter.com/biorxivpreprint/status/1314766530765295618 ). "chimerism", broadly speaking, is inclusive of cells "transferring mitochondria" to other cells, cells "transferring telomere to other cells", AAV'ing or CMV'ing genes [like enhanced SIRT6] from centenarians or bowhead whales into humans.

Even glial cells and astrocytes can be "reprogrammed" into neurons (though whether they will retain the information is another issue), and there are ways for cells to "expel" their aggregates/debris to be cleared up or removed by macrophages/astrocytes/cerebrospinal fluid (hell, even the Li-Huei Tsai lab has shown that playing 60Hz frequencies can help remove amyloid plaque from neurons). One of the real questions I have is whether there is a way for a cell to expel all kinds of intracellular junk, including the notoriously impliable lipofuscin and ceroid aggregates (there's a kind of lipid/protein structure that is amenable to being engulfed by exosomes that can clear out the damage). 

it's important to note that bowhead whales can live to 200+ years even without obvious age-associated pathology, and we may be better prodded to build more "robust" mitochondria/cell membranes just by studying them (eg degree of membrane unsaturation seems anticorrelated to longevity in organisms like birds), and we can simply try to make our cell membranes less prone to ROS (one way is to incorporate deuterated PUFAs/omega-3's), which somehow still does not get as much research as claimed [some degree of enhanced deuteration is also helpful for longevity].

Overall you want to maintain the cell's ability to sense damage and to properly reduce this damage before it reaches high levels [genomic damage/mosaicism is the hardest to sense, but this is ultimately a more distal problem than more immediate problems that come from loss of proteostasis]